Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells

Krebs, Danielle L.; Chehal, Manreet K.; Sio, Alexander; Huntington, Nicholas D.; Da, Mei Lin; Ziltener, Pascal; Inglese, Melissa; Kountouri, Nicole; Priatel, John J.; Jones, Juli E.; Tarlinton, David M.; Anderson, Gary P.; Hibbs, Margaret L.; Harder, Kenneth W.

doi:10.4049/jimmunol.1103395

Cited by 23 publications

(21 citation statements)

References 85 publications

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“…5E, 5F), suggesting that Lyn-deficient DCs are sensitized to have enhanced responses to endogenous or ubiquitous TLR ligands, and are a major producer of pro-inflammatory cytokines in these mice. This is in agreement with other recent reports describing a pro-inflammatory role of Lyn-deficient DCs (10, 11). As mentioned above, the incidence of splenomegaly was greatly reduced in aged (~10 month) Lyn −/− DC-MyD88 −/− mice compared with Lyn −/− mice (Fig.…”

Section: Resultssupporting

confidence: 94%

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Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Hua

Gross

Lamagna

et al. 2014

The Journal of Immunology

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The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn−/− mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR signaling pathways have been implicated in the production of anti-nuclear antibodies in SLE and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn−/− mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear antibodies, as well as the deposition of these antibodies in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn−/− mice were completely abolished by selective deletion of Myd88 in B cells and the autoantibody production and glomerulonepritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease of the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn−/− mice may depend on GC responses. Consistent with this view, IgG anti-nuclear antibodies were absent if T cells were deleted (TCRβ−/− TCRδ−/− mice) or if T cells were unable to contribute to GC responses due to mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn−/− mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model whereby DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell-dependent systemic autoimmunity in Lyn−/− mice.

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Section: Resultssupporting

confidence: 94%

“…Several recent studies have implicated dysregulation of DCs by loss of Lyn as also being an important contributor to the autoimmune phenomena in Lyn −/− mice (10, 11). Consistent with this view is our demonstration that MyD88 signaling in DCs contributes importantly to the autoimmune phenotypes of Lyn −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Hua

Gross

Lamagna

et al. 2014

The Journal of Immunology

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“…Lyn knockdown completely abolished ERK1/2 phosphorylation (50). Lyn attenuated NF-κB signaling and up-regulated Lyn exhibited weak NF-κB activation (51). We showed that Lyn-deficiency increased the expression of Smad2, STAT6, and NFκB as well as phosphorylation of Smad2, STAT6, and NFκB.…”

Section: Discussionmentioning

confidence: 99%

Lyn Mitigates Mouse Airway Remodeling by Downregulating the TGF-β3 Isoform in House Dust Mite Models

Fox

Liu

et al. 2013

The Journal of Immunology

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Chronic airway remodeling is a serious consequence of asthma, which is caused by complex but largely unknown mechanisms. Despite versatile functions, the role of Lyn in chronic airway remodeling remains undefined. Using Lyn−/− mice, we show that continual exposure (for 8 weeks) of house dust mite (HDM) extracts induced a severe phenotype of chronic airway remodeling including exacerbated mucus production, collagen deposition, dysregulated cytokine secretion, and elevated inflammation. Strikingly, a significant increase in TGF-β3 rather than TGF-β1 was observed in Lyn−/− mouse lungs compared to wild-type mice. Furthermore, TGF-β3 neutralizing antibodies not only inhibited the expression of STAT6 and Smad2/3, but also decreased phosphorylation of Smad2 and NFκB in Lyn−/− mouse lungs. In addition, both recombinant and adenoviral TGF-β3 significantly promoted epithelial to mesenchymal transition (EMT) and intensified collagen I production and MUC5AC expression. Further examining chronic asthma patients showed that a decreased Lyn correlated with the severity of airway inflammation and mucus hypersecretion. Finally, Lyn may critically regulate airway remodeling by directly interacting with TGF-β3. Collectively, these findings revealed that Lyn regulates TGF-β3 isoform and modulates the development of airway remodeling, which may have therapeutic indications for severe chronic asthma.

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“…TLR2/4/6, cytokine receptors (CXCR4, receptors for IL-3, IL-5, CSF2) and growth factors in platelets, neutrophils and eosinophils (e.g. 87,88 ). ADAM9 (Disintegrin and metalloproteinase domain-containing protein 9) cleaves multiple substrates involved in angiogenesis, may act as an alpha secretase for APP and has been involved in viral infection mechanisms 89 complex which directs endosomes towards lysosome and is crucial in multivesicular body formation.…”

Section: Nsp14 Associates With Rna Decapping and Deadenylation Host Fmentioning

confidence: 99%

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Laurent

Sofianatos

Komarova

et al. 2020

Preprint

128

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The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

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Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells

Cited by 23 publications

References 85 publications

Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

Lyn Mitigates Mouse Airway Remodeling by Downregulating the TGF-β3 Isoform in House Dust Mite Models

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

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